1. Field of the Invention
The invention relates to neuronal cell transplantation for neurodegenerative conditions of the central nervous system including hypoxia-ischemia (stroke), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease and other forms of dementia and, more specifically, to methods of producing populations of neurons by manipulating the myocyte enhancer factor 2 (MEF2) transcription pathway.
2. Background Information
For a variety of serious neurodegenerative diseases, there exist no effective therapies or cures. For example, Parkinson's disease is a progressive and ultimately fatal neurodegenerative disorder characterized by loss of the pigmented dopaminergic neurons of the substantia nigra. The symptoms of Parkinson's disease can often be managed initially by administration of L-DOPA, the immediate precursor of dopamine. However, reduced efficacy of L-DOPA treatment typically occurs over time. Programmed cell death (apoptosis) has been implicated in this neurodegenerative disorder.
In Alzheimer's disease, the most common neurodegenerative disease and most frequent cause of dementia, progressive failure of memory and degeneration of temporal and parietal association cortex result in speech impairment and loss of coordination, and, in some cases, emotionally disturbance. Alzheimer's disease generally progresses over many years, with patients gradually becoming immobile, emaciated and susceptible to pneumonia.
The brain constitutes a privileged transplantation site and, under the appropriate conditions, neuronal tissues can survive transplantation into the damaged brain, integrate with the host and alleviate functional impairments associated with neurological disease. Neuronal cell transplantation has been sought for a variety of serious neurodegenerative diseases for which no effective therapeutic course exists, including Parkinson's disease and Alzheimer's disease as well as Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and pain.
Present techniques for neuronal transplantation have chiefly relied on embryonic or fetal tissues since central nervous system (CNS) neurons only survive transplantation if taken from embryonic or neonatal donors. Neuronal transplantation has been hampered by extremely limited supplies of human embryonic or fetal tissue. In order to develop alternative supplies of donor neurons, scientists have attempted the large scale expansion of stem cells and precursor cells. When treated with high doses of epidermal growth factor, stem and precursor cells from the brain can be selectively expanded in vitro and grown exponentially through multiple passages. These expanded cells, which can be produced from human tissues, yield both neuronal and glial cell types when allowed to differentiate in vitro and survive transplantation back into animal central nervous system (CNS; Svendsen et al., Exp. Neurol. 140:1-13 (1996)).
Unfortunately, the expansion of stem and precursor cell populations currently does not produce a cell population useful for therapeutic transplantation, since a relatively small number of neurons is produced, and even a smaller number survive and express the neuronal phenotype when grafted into the central nervous system. Thus, there is a need for a method of efficiently producing large numbers of neuronal cells or their precursors which are capable of surviving when transplanted into the central nervous system in vivo. The present invention satisfies this need and provides related advantages as well.